Hydrazines hydroxamic acids

Me3Si)2NH, Me3SiCl, Pyr, 20°, 5 min, 100% yield. ROH is a carbohydrate. Hexamethyldisilazane (HMDS) is one of the most common sily-lating agents and readily silylates alcohols, acids, amines, thiols, phenols, hydroxamic acids, amides, thioamides, sulfonamides, phosphoric amides, phosphites, hydrazines, and enolizable ketones. It works best in the presence of a catalyst such as X-NH-Y, where at least one of the group X or Y is electron-withdrawing. ... 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

Hydroxamic acids are an important class of compounds targeted as potential therapeutic agents. A-Fmoc-aminooxy-2-chlorotrityl polystyrene resin 61 allowed the synthesis and subsequent cleavage under mild conditions of both peptidyl and small molecule hydroxamic acids (Fig. 14) [70]. An alternative hydroxylamine linkage 62 was prepared from trityl chloride resin and tV-hydroxyphthalimide followed by treatment with hydrazine at room temperature (Scheme 30) [71]. A series of hydroxamic acids were prepared by the addition of substituted succinic anhydrides to the resin followed by coupling with a variety of amines, and cleavage with HCOOH-THF(l 3). 

Enzymatic transformations of alkaloids by peroxidases most probably occur by single-step oxidations catalyzed by the HRP-I and HRP-II forms of the enzyme. The catalysis of one-electron oxidations of compounds containing aromatic hydrocarbon, hydrazine, phenol, hydroxamic acid, and amine functional groups has been recently reviewed (45, 58, 82). A brief summary of those HRP reactions that involve functional groups most commonly occurring in alkaloids is presented below. 

Hence, the implication of combinatorial chemistry for high throughput generation of structurally diverse hydroxamic acids is self-evident. Several solid-phase approaches for their syntheses have been reported,1 7-11 the majority of which are based on the anchoring of iV-hydroxyphthalimide onto an appropriate solid support. After hydrazine-mediated /V-dcprotcction, /V-acylation of the resin-bound hydroxylamine would yield the desired O-anchored hydroxamic acid, which is typically released by acidolysis. 

Acylhydrazines R1 CONF1NF1R2 (R1 = Ph or PhCH2 R2 = Bu, PhCH2 or Ph) are produced by the action of hydroxamic acids R ONHOH on the primary amines R2NH2 in the presence of tosyl chloride or 2-chloro-l-methylpyridinium chloride94. O-(Diphenylphosphinoyl)-A-arylhydroxylamines 77 (R = NO2, Ac, Tos or CN) react with A-methylaniline to afford the hydrazine derivatives 7895. 

A-Hydroxyphthalimide 178 was used as a source of the hydroxylamine reacting with trityl chloride resin 182 in the presence of triethylamine to obtain the A-hydroxyphth-alimide derivative 183. This intermediate is transformed to the desired hydroxylamine resin 184 by treatment with hydrazine. The peptidic and peptidomimetic hydroxamic acids 185 and 186 were synthesized using the described solid-supported reagent (Scheme 82). 

Hydroxylamines and hydrazines can be acylated on insoluble supports using the same type of acylating agent as is used for the acylation of amines [146-149]. Because of their higher nucleophilicity, hydroxylamines or hydrazines can be acylated more readily than amines, and unreactive acylating agents such as carboxylic esters can sometimes be successfully employed (Table 13.10). Polystyrene-bound O-alkyl hydroxamic acids can be N-alkylated by treatment with reactive alkyl halides and bases such as DBU (Entry 5, Table 13.10). 

The hydrolysis of esters (and amides) by chymotrypsin satisfies these criteria. The hydrolysis of, say, acetyl-L-tryptophan p-i itrophenyl ester forms an acylen-/yme that reacts with various amines such as hydroxylamine, alaninamide, hydrazine, etc., and also with alcohols such as methanol, to give the hydroxamic acid, dipeptide, hydrazide, and methyl ester, respectively, of acetyl-L-tryptophan. The same acylenzyme is generated in the hydrolysis of the phenyl, methyl, ethyl, etc., esters of the amino acid (and also during the hydrolysis of amides). 

If primary or secondary amines are used, AT-substituted amides are formed. This reaction is called aminolysis. Hydrazines yield the corresponding hydrazides, which can then be treated with nitrous acid to form the azides used in the Curtius rearrangement. Hydroxyl amines give hydroxamic acids. 

Electrophilic N-aminations have been performed with hydroxylamine-O-sulfonic acid (HOSA)," O-(2,4-dinitrophenyl)hydroxylamine and C>-mesitylenesulfonylhydroxylamine. The use of HOSA is mainly restricted to aqueous reaction media. Imide sodium salts of some heterocycles such as theobromine (88) can be converted to hydrazine derivatives by treatment with 0-(diphenylphosphinyl)hydroxylamine (equation 35)." This reaction has been extended to synthesis of N-arylhyd ines, where R and R are hydrogen, alkyl or aryl (equation 36)." Similarly, trisubstituted hydrazines can be prepared by the use of N-aryl-O-acetylhy oxylamines and secondary amines." A recent publication" concerning the synthesis of l-acyl-2-dkylhydrazines from hydroxamic acids and amines in the presence of activating agents has been found to be erroneous no N—N bond formation occurs under these conditions." ... 

Salts of thiols (170) oi of sulfinic acids (171) react like the alkoxides, giving 4-alkylthio- oi 4-alkylsulfono-suhstituted butyrates. Alkali cyanides give 4-cyanobutyrates (172), hydroxylamine gives a hydroxamic acid (173), and hydrazine a hydrazide (174). 

Dinitrosyl complexes of the type [Mo°(NO)2X2] were obtained by reduction of [Mo04] by hydroxylamine in the presence of added anionic ligands X, where X = dithiocarbamate, dithiocarboxylate, alkoxide, 2-NH2C6H4E (E = O or S), hydroxamic acids. Reaction of [Mo(NO)2 (dttd)] (dttd = (22)) with hydrazine or NaBH4 gave the k -hydroxylamide, [Mo(NO) (ONH2) (dttd)]. 

Tepoxalin is a potent inhibitor of both the cyclcooxygenase and lipoxygenase pathways of the arachidonic acid cascade. In a facile and more environmentally friendly synthesis, condensation between methoxyphenyl-hydrazine and the bis-ketone with a pendant hydroxamic acid group at the end of the molecule delivered tepoxalin in 70% yield. 

The final item in Table 9.9 resembles that of Scheme 9.151. However, whereas hydrazine (H2NNH2) was the species that substituted for the ethoxy group (-OCH2CH3) in that scheme, hydroxylamine (HONHj) is used in item 12 of Table 9.9 to generate the hydroxamic acid. 

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